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Process for manufacturing bisphosphonic acids

a technology of bisphosphonic acid and industrial process, which is applied in the field of improved industrial process for the preparation of bisphosphonic acid, can solve the problems of uncontrolled exotherm, safety concerns, and solidification of reaction melt, and achieve the effect of easy adaptation to manufacture other bisphosphonic acids

Inactive Publication Date: 2009-05-28
ALBEMARLE CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0007]Accordingly, the present invention provides a manufacturing process for the preparation of bisphosphonic acids and in particular zoledronic acid. While the description that follows relates specifically to the manufacture of zoledronic acid, the process may be easily adapted to manufacture other bisphosphonic acids by selecting the appropriate starting materials.

Problems solved by technology

One problem associated with this process involves the solidification of the reaction melt.
Unfortunately, methanesulfonic acid reacts with phosphorus trichloride and under adiabatic conditions the reaction becomes self-heating at 85° C. and an uncontrolled exotherm occurs at >140° C.
However, these systems present various drawbacks including safety concerns, high costs, product contamination, and / or additional processing steps.
However, when employed with the process of the present invention, the yield and purity were unsatisfactorily low.

Method used

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  • Process for manufacturing bisphosphonic acids
  • Process for manufacturing bisphosphonic acids
  • Process for manufacturing bisphosphonic acids

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Imidazoleacetic Acid

[0016]A 50 L reactor was charged with chloroform (54 kg), imidazole (6.13 kg, 90.04 mol) and t-butyl chloroacetate (5.48 kg, 36.4 mol). The temperature was increased to 60° C. over a 2 hour period and maintained at 60° C. for an additional 24 hours. The reaction mass was cooled to room temperature. The chloroform phase was washed successively with four portions of water (7.2 kg each) to remove imidazolium salts and excess imidazole.

[0017]Water (15.1 kg) was added and chloroform was removed by distillation with a jacket temperature of 60-65° C. (53° C. is the boiling point of the azeotrope) using a Dean-Stark trap to return the water phase. After chloroform was removed, the reactor jacket temperature was slowly raised to 115° C. during which time t-butanol and water co-distilled (azeotrope boiling point is 80° C.). After the alcohol was removed, the aqueous solution was cooled and drained from the reactor, giving 17.54 kg of solution containing imid...

example 2

Isolation of Imidazoleacetic Acid

[0018]A portion of the solution from Example 1 (1.13 kg) was rotary evaporated to give a slurry of solids (0.38 kg) to which was added acetone (234 g) to complete crystallization. The solid was filtered, washed with acetone and dried with a stream of nitrogen. The evaporator condensate was re-evaporated, washed and dried to give a second crop of crystals; this was combined with the first, to give imidazoleacetic acid (219 g, 91% recovery, 98.9 wt % pure by NMR assay). 1H NMR (D20): 8.68 (s, 1H); 7.42 (s, 2H); 4.83 (s, 2H); 4.79 (br s, 1H).

example 3

Preparation of Zoledronic Acid

[0019]A 1.5 liter kettle reactor, fitted with a heating mantle, mechanical stirrer, dropping funnel, thermocouple and condenser with nitrogen inlet adapter, was charged with imidazoleacetic acid (100 g, 0.793 mol), diglyme (400 ml), and 85% phosphoric acid (55 ml). Phosphorus trichloride (330 g, 2.41 mol) was slowly added to the reaction mass resulting in an exotherm and the evolution of hydrogen chloride. The temperature was allowed to rise to 70° C. and the solution was stirred until the evolution of HCl subsided. The temperature of the reaction mass was increased to 85° C. and a white solid began to form, float and adhere to the stirrer shaft. After about 1 hour, stirring became impossible and the stirring motor was stopped. The reaction mass was heated for 5 more hours at 85° C. and then cooled to ambient temperature, producing a solid homogeneous white mass.

[0020]Water was slowly added to the white mass (320 ml) that resulted in an exotherm and HCl...

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PUM

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Abstract

A manufacturing process for the preparation of bisphosphonic acids and in particular zoledronic acid is provided wherein diglyme, monoglyme, or a mixture thereof, is utilized to produce a homogenous, water soluble, solid reaction mass that upon cooling, dissolving in water and stripping results in a high purity product and comparatively good yield. wherein Ri is selected from the group consisting of

Description

BACKGROUND OF THE INVENTION[0001]The present invention relates to an improved industrial process for the preparation of bisphosphonic acids and their pharmacologically active salts, and in particular, 1-hydroxy-2-(imidazol-1-yl)ethylidene-1,1-bisphosphonic acid, commonly referred to as zoledronic acid. The bisphosphonic acids described herein are suitable for the treatment of diseases of the skeletal system and in cases when bone formation and / or calcium metabolism have been disturbed, such as in the therapy of bone metastases.[0002]The bisphosphonic acids described herein have the following structure:wherein M1, M2, M3 and M4 are selected from hydrogen and a monovalent cation and R1 can be one of the following:[0003]U.S. Pat. Nos. 4,939,130 and 4,777,163 disclose a process for making bisphosphonic acids based upon a known method published by Kabachnick et al. [Izv. Akad. Nauk. USSR, Ser. Khim., 2, 433-437, (1987)]. The synthesis basically consists of reacting the appropriate w-amin...

Claims

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Application Information

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IPC IPC(8): C07D221/02C07D233/54C07D213/02C07F9/38
CPCC07F9/386C07F9/3873C07F9/6561C07F9/65061C07F9/582C07F9/58C07F9/6506
Inventor SAMSEL, EDWARD G.WU, TSE-CHONG
Owner ALBEMARLE CORP
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